PMID- 7870895
OWN - NLM
STAT- MEDLINE
DCOM- 19950329
LR  - 20190726
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 110
IP  - 1-2
DP  - 1993
TI  - Comparison of in vitro binding properties of a series of dopamine antagonists and 
      agonists for cloned human dopamine D2S and D2L receptors and for D2 receptors in 
      rat striatal and mesolimbic tissues, using [125I] 2'-iodospiperone.
PG  - 27-36
AB  - We investigated the ligand binding properties in vitro of two splice variants of 
      the cloned human dopamine D2 receptor (the 443 and 414 amino acids long forms 
      called D2L and D2S, respectively), expressed in 293 human kidney cells, in 
      comparison with those of the dopamine D2 receptors in rat striatum, nucleus 
      accumbens and tuberculum olfactorium. The new radioligand, 
      [125I]2'-iodospiperone, showed a similar high binding affinity (KD:0.056-0.122 
      nM) for cloned human D2S and D2L receptors and for the D2 receptors in the three 
      rat brain areas. Binding affinities of 25 dopamine antagonists and of 10 dopamine 
      agonists belonging to different chemical classes were measured. The IC50 values 
      of the antagonists were virtually identical in the five preparations: spiperone 
      was the most potent compound (pIC50 approximately 9.9), remoxipride the least 
      potent one (pIC50 approximately 5.7). The agonists showed similar IC50 values for 
      the cloned human D2S and D2L receptors but their affinity for rat brain D2 
      receptors was 2- to 5-fold higher. Dopamine showed shallow inhibition curves, the 
      high affinity binding was 10-fold lower for the cloned human D2 receptors than 
      for the rat brain D2 receptors. Addition of stable guanosine-5'-triphosphate 
      (GTP) analogues shifted the D2 receptors in the rat brain tissues to the "low" 
      affinity state, the low affinity binding of dopamine was equal to the affinity 
      for the cloned human receptor. None of the dopamine antagonists or agonists could 
      differentiate between the two splice forms of the cloned human D2 receptors or 
      between the D2 receptors in rat striatal and mesolimbic tissues. The lower 
      apparent affinity of some agonists and of dopamine in the absence of stable GTP 
      analogues suggests a less appropriate receptor G-protein coupling for the cloned 
      human D2 receptors expressed in the 293 human kidney cells. Unexpectedly, 
      guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma-S) reduced the 
      [125I]2'-iodospiperone binding to the D2 receptors by 20-35% in the rat brain 
      tissues and the cloned human D2L receptor, and by 75% to the cloned human D2S 
      receptor. The inhibition in the last case could be prevented partly by 
      submicromolar concentrations of dopamine. The GTP-gamma-S effect is suggested to 
      be due to reduction of disulphide bonds in the receptor. Recent molecular 
      modelling studies indicated an important role of the disulphide bridge between 
      Cys107 at the start of transmembrane domain three and Cys182 in the third 
      extracellular loop, for the binding of dopamine to the D2 receptor.
FAU - Leysen, J E
AU  - Leysen JE
AD  - Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, 
      Belgium.
FAU - Gommeren, W
AU  - Gommeren W
FAU - Mertens, J
AU  - Mertens J
FAU - Luyten, W H
AU  - Luyten WH
FAU - Pauwels, P J
AU  - Pauwels PJ
FAU - Ewert, M
AU  - Ewert M
FAU - Seeburg, P
AU  - Seeburg P
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Dopamine Agonists)
RN  - 0 (Dopamine Antagonists)
RN  - 0 (Iodine Radioisotopes)
RN  - 0 (Ligands)
RN  - 0 (Receptors, Dopamine D2)
RN  - 103445-60-9 (2'-iodospiperone)
RN  - 4X6E73CJ0Q (Spiperone)
RN  - 86-01-1 (Guanosine Triphosphate)
SB  - IM
MH  - Animals
MH  - Cloning, Molecular
MH  - Dopamine Agonists/*metabolism
MH  - Dopamine Antagonists/*metabolism
MH  - Female
MH  - Guanosine Triphosphate/analogs & derivatives/pharmacology
MH  - Humans
MH  - Iodine Radioisotopes
MH  - Ligands
MH  - Limbic System/drug effects/*metabolism
MH  - Neostriatum/drug effects/*metabolism
MH  - Nucleus Accumbens/drug effects/metabolism
MH  - Olfactory Bulb/drug effects/metabolism
MH  - Pituitary Gland/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Dopamine D2/*metabolism
MH  - Spiperone/*analogs & derivatives/pharmacokinetics
EDAT- 1993/01/01 00:00
MHDA- 1993/01/01 00:01
CRDT- 1993/01/01 00:00
PHST- 1993/01/01 00:00 [pubmed]
PHST- 1993/01/01 00:01 [medline]
PHST- 1993/01/01 00:00 [entrez]
AID - 10.1007/BF02246947 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 1993;110(1-2):27-36. doi: 10.1007/BF02246947.